High or excessive anxiety is a major symptom of many neuropsychiatric disorders. The search for anti-anxiety drugs without the side effects of traditional benzodiazepines has led to the discovery of a partial serotonin 1A agonist (buspirone) as an efficient, relatively safe anxiolytic. Recently, 5-HT1A receptor null mutant mice have been generated. These animals display high anxiety-like behaviors and low locomotor activity while appearing otherwise normal. This proposal outlines experiments designed to characterize the molecular, cellular and physiological changes that are the consequences of the receptor deficit and that may underlie this phenotype (Aims 1 and 2). The third aim of this study consists of evaluating the responses of these mice to various anxiolytic drugs in behavioral models of anxiety. A long-term goal is to fully assess the 5-HT 1A receptor knockout mice as putative animal models, not only for screening potential compounds for anxiolytic effects, but also to decipher the molecular mechanisms that underlie this anxiety trait. Such mechanisms may represent molecular targets for therapeutic approaches.